Surfactant-associated protein D (SP-D) plays diverse roles in host defense, innate immunity, and pulmonary homeostasis - including responses to viral challenge. SP-D can specifically neutralize a variety of respiratory viruses, enhance the clearance of apoptotic cells, and modulate the proliferation and function of immune effector cells. Using the murine model of paramyxovirus-induced chronic airway remodeling, we recently observed marked increases in the production of SP-D by the airway epithelium, both at early and late time points following challenge. Notably, areas of SP-D overexpression co-distributed with areas of goblet cell metaplasia. Previous studies have shown that late airway remodeling includes a genetic backgrounddependent epithelial response primarily mediated by decreased apoptosis of airway epithelial cells, and associated with alterations in mucin expression. The latter is mediated in large part by IL-13 via the IL-4/IL- 13 receptor, a pathway that also contributes to the regulation of SP-D expression. Interactions of SP-D with viral pathogens are largely determined by interactions with the trimeric C-terminal, carbohydrate recognition domain (CRD). We hypothesize that recognition of viral envelope proteins involves multiple sites of interaction between the SP-D lectin domain and specific high mannose glycans, that airway SP-D can modulate epithelial responses to virus, and that CRD-dependent interactions with secreted host molecules can modify SP-D activity. Accordingly, we propose four specific aims: 1. to examine the expression of SP-D by the bronchiolar epithelium, both in normal mice and in the context of challenge with RNA viruses; 2. to further define mechanisms of SP-D recognition of viral glycans by SP-D and the effects of viral interactions on the epithelial response to virus; to further characterize the specific interactions of SP-D with apoptotic epithelial cells and examine potential anti-apoptotic effects of the lung collectins; and to characterize the interactions of SP-D with endogenous ligands that are expressed in the distal airways. To achieve these aims, we will combine state of the art cell culture and murine models with array-based glycomic analysis, functional assays, and crystallographic correlation. The proposed studies will increase our understanding of the contributions of SP-D to anti-viral host defense and the regulation of pulmonary homeostasis at the level of the distal airways, and yield important new and mechanistic information relating to SP-D function at the atomic and molecular level. This is highly relevant to a wide variety of human infectious and/or immune mediated airways diseases.